Patient‐controlled analgesia with remifentanil versus alternative parenteral methods for pain management in labour
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To systematically assess the effectiveness of remifentanil PCA for labour analgesia, along with any potential harms to the mother and the baby.
Background
Nowadays, multiple strategies are available to provide pain relief during labour, such as central neuraxial analgesia (e.g. epidural analgesia), parenteral opioids, and inhalational analgesia. According to the guidelines of the American Society of Anaesthesiologists (ASA) and the College of Obstetricians and Gynaecologists (ACOG), epidural analgesia is recommended as the most flexible, effective and least depressing to the central nervous system analgesic modality in obstetrics (Goetzl 2002). However, obstetric anaesthesiologists are occasionally faced with women who cannot receive this type of labour analgesia due to absolute or relative contraindications, e.g. woman receiving prophylactic anticoagulants (Moghbeli 2008), or women with significant coagulation disorders. Pregnant women may also ask for alternatives to central neuraxial analgesia for personal reasons. Moreover, central neuraxial analgesia may also technically not be possible to perform in women requesting pain relief for labour. Finally, there are many places in the world which do not offer epidural pain relief either at all, or only on a very limited basis (Saravanakumar 2007).
A common method for pain relief in labour is the use of opioids (e.g. pethidine) administered either via the intravenous (IV) or intramuscular (IM) route. In 2008, a survey in the United Kingdom on the prescription of IM opioids (e.g. pethidine) for labour analgesia concluded that pethidine lacks efficacy as an analgesic and has adverse effects on both the mother and the neonate (Tuckey 2008). Nevertheless, pethidine, morphine or diamorphine, and other long‐acting opioids are still frequently used (Tuckey 2008); a situation that does not differ markedly when compared with other European countries (Schnabel 2011).
These findings are in notable contrast to German and other European countries’ guidelines on acute pain relief. Concerning the use of pethidine, the German guidelines on the management of acute pain relief in labour recommend that pethidine is not suited due to neurotoxic effects. Especially for the IM application route of pethidine, a negative recommendation (“Grade of Recommendation: A”) was stated (AWMF guidelines 2009, AWMF‐Register Nr. 001 ‐ 025, download on 29.11.2011).
Another alternative for labour analgesia is achieved by inhalational analgesia using e.g. nitrous oxide. In principle, this method ensures that the mother stays awake and laryngeal reflexes remain intact. The fact that inhaled interventions for pain relief are usually easy to administer with limited preparation time and fast onset account for their popularity in some countries (Irestedt 1994; Kranke 2013). However, the existing body of evidence with respect to nitrous oxide and other inhaled molecules has been the subject of two systematic reviews with controversial results concerning the effectiveness as labour analgesic (Klomp 2012; Rosen 2002).
The described discrepancy between scientific evidence and recommendations on the one hand, and the current clinical practice on the other hand, demands a closer look at the current body of evidence to discover alternative techniques that might be promising in view of efficacy (pain relief) and safety for both the mother and the neonate. For several reasons described above, there is an urgent need for an effective and safe systemic analgesic for labour pain, which can be used as an alternative to central neuraxial analgesia in obstetrics. Due to its unique pharmacodynamic and pharmacokinetic profile (fast on‐ and offset), remifentanil might be an alternative opioid for labour analgesia (Egan 1993). Several surveys and narrative reviews focusing on opioids in obstetrics showed that remifentanil is gaining popularity (Lavand'homme 2009).
Proponents of the use of remifentanil for labour analgesia claim that it should be routinely available as an alternative for labour analgesia in those women who either do not want, can not have, or do not need, epidural analgesia (Hill 2008). However, opponents argue that not only does remifentanil produce negative respiratory effects for both the mother and the neonate, but also that the available evidence supporting the use of remifentanil is limited (Van de Velde 2008).
Therefore, it is essential to develop an evidence‐based decision basis for labour pain management and to promote a shared decision‐making process with parturients. In case of superiority of newer, more efficient and safer techniques, these techniques should be implemented when possible and safe to avoid unnecessary suffering and decrease potential negative impact on parental as well as neonatal outcomes.
Description of the condition
Pain during labour can be very intense and many pregnant women are anxious about the pain they will experience. This holds true also for women who have received prepared childbirth training (Melzack 1984). The anatomic and neurophysiologic basis underlying the pain of childbirth along with different pain‐management strategies are described in detail in an overview of systematic reviews dealing with pain management for women in labour (Jones 2012). The choice and demands of pain relief differ between countries and cultures and likewise the willingness to face and endure labour pain (Callister 2003; Callister 2010; Kartchner 2003; Semenic 2004; Weber 1996; Wilkinson 2010). Labour pain may be associated with adverse effects on both the mother and the fetus, mainly by elevated plasma catecholamine levels, respiratory changes and associated shifts in pCO2 and pH. Furthermore, intense pain may also result in prolonged labour (Reynolds 2011). Therefore, it is important to provide women with various options for pain control during labour.
Description of the intervention
Remifentanil, first described in 1991 (James 1991), is a very short‐acting opioid with an analgesic potency that is about 200 times higher compared to morphine (Westmoreland 1993). It acts as a specific agonist on the μ‐opioid‐receptor. The metabolisation of remifentanil through nonspecific tissue and plasma esterases decreases its half‐life to only a few minutes, leading to a rapid decline of action in the patient. The fast on‐ and offset of the drug action implies an improved controllability in contrast to more traditional opioids with long‐lasting action (Leong 2011). Especially, when applied in a patient‐controlled manner, remifentanil analgesia allows enhanced flexibility and controllability for obstetrics. The action of remifentanil, as well as safety concerns are not affected by impaired liver or kidney function of the recipients (Bosilkovska 2012; Hohne 2004). Known side effects of remifentanil include respiratory depression, nausea, pruritus, and decreased heart rate and blood pressure. It is mostly used in anaesthesiology, e.g. as a component of total intravenous anaesthesia (TIVA) combined with propofol due to its predictable pharmacokinetics irrespective of organ function and the lack of accumulation. Owing to the unique pharmacodynamic and pharmacokinetic characteristics of remifentanil, it is increasingly used for labour pain relief. The comparable rapid metabolisation of IV‐administered remifentanil in adults and neonates suggests only a limited risk to cause prolonged side effects for the newborn.
How the intervention might work
Remifentanil has been used for anaesthesia for many years, providing effective and controllable analgesia for different kinds of surgical procedures by acting as a μ‐agonist. In labour, remifentanil appears to have a more pronounced and satisfying analgesia compared to other opioids (Glass 1993). Due to its characteristics (fast onset, short half‐life), it can be administered in a patient‐controlled mode, giving the parturient the opportunity of pain relief when required. Therefore, remifentanil might be an alternative to other opioids and to epidural analgesia.
Why it is important to do this review
Remifentanil patient‐controlled analgesia (PCA) for labour analgesia is becoming increasingly popular in some countries, while in other countries there is a remaining reluctance towards its use due to the fear of possible adverse effects based on few reported severe outcomes secondary to remifentanil administration for labour pain (Bonner 2012; Pruefer 2012). Previously, some of the published trials have been partially summarised in systematic reviews, which either deal with the comparison of remifentanil PCA versus epidural analgesia (Liu 2014), or remifentanil versus pethidine (Leong 2011), or both of those comparisons in addition to fentanyl and nitrous oxide as comparators (Schnabel 2011) in the obstetrics setting. However, none of those reviews, in contrast to the current protocol, defined adverse events associated with this intervention as their primary outcome. Moreover, an up‐to‐date systematic review with the comprehensive reporting and high‐quality standard of a Cochrane review, including the commitment for a subsequent update process, is still lacking.
Objectives
To systematically assess the effectiveness of remifentanil PCA for labour analgesia, along with any potential harms to the mother and the baby.
Methods
Criteria for considering studies for this review
Types of studies
We will include individually randomised controlled trials (RCTs) and cluster‐randomised trials. Cross‐over trials and quasi‐RCTs will not be included. Trials which are only published in abstract form will be included, if sufficient information in the abstract is available to allow an assured decision on inclusion.
Types of participants
All women in labour with planned vaginal delivery, including high‐risk groups, e.g. preterm labour or following induction of labour.
We will not include women scheduled for caesarean delivery.
Types of interventions
We will compare remifentanil administered via a patient‐controlled analgesia (PCA) device versus:
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placebo or no treatment;
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another opioid using the same mode of administration (PCA or continuous infusion);
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another opioid using a different mode (nurse‐/midwife‐controlled, short infusion) or route (IM/subcutaneous (SC)) of administration;
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epidural analgesia or other central neuraxial blocks (e.g. combined spinal epidural (CSE));
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nitrous oxide (or other forms of inhalational analgesia);
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remifentanil using a different mode (continuous IV administration) of administration;
We will include trials describing all modes of IV pain control with remifentanil using a PCA pump at any stage during labour. There will be no restrictions regarding the lockout‐interval, the amount of remifentanil delivered with each bolus dose, whether adjusted doses due to the patient’s body weight, e.g. 0.5 μg/kg of actual/ideal body weight, or a dosing scheme with increasing doses depending on the efficacy in order to find if the appropriate dose were applied. Further, we will include trials investigating regimen with only bolus doses as well as trials investigating regimen that combine a defined amount of continuous administration of remifentanil with additional bolus doses of remifentanil upon request.
Both the bolus doses as well as the basal rates may be steady or variable over the course of time. In the intervention group, no other analgesics are allowed for simultaneous administration. However, this does not exclude the prior use of other parenteral (opioid) analgesics or other methods of pain relief being administered to the parturients.
Types of outcome measures
Primary outcomes
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Satisfaction with pain relief (as defined by trialists)
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Adverse events for women (e.g. apnoea, respiratory depression, oxygen desaturation, hypotension, bradycardia, nausea, vomiting, postpartum haemorrhage, maternal somnolence)
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Adverse events for the newborn (e.g. Apgar scores less than seven at five minutes, need for naloxone, depressed baby, opioid‐induced loss of fetal heart rate variability)
Secondary outcomes
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Pain intensity (as defined by trialists)
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Additional analgesia required (e.g. conversion to epidural analgesia)
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Rate of caesarean delivery
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Rate of assisted vaginal birth
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Satisfaction with childbirth experience (as defined by trialists)
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Sense of control in labour
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Effect (negative) on mother/baby interaction
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Breastfeeding initiation (as defined by trialists)
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Umbilical cord base excess (arterial and venous)
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Umbilical cord pH (arterial and venous)
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Need for neonatal resuscitation (e.g. CPAP (Continuous Positive Airway Pressure), bag or mask ventilation, intubation)
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Long‐term childhood development (as defined by trialists)
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Cost (as defined by trialists)
Search methods for identification of studies
The following methods section of this protocol is based on a standard template used by the Cochrane Pregnancy and Childbirth Group.
Electronic searches
We will contact the Trials Search Co‐ordinator to search the Cochrane Pregnancy and Childbirth Group’s Trials Register
The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co‐ordinator and contains trials identified from:
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monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
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weekly searches of MEDLINE (Ovid);
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weekly searches of Embase (Ovid);
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monthly searches of CINAHL (EBSCO);
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handsearches of 30 journals and the proceedings of major conferences;
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weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.
Details of the search strategies for CENTRAL, MEDLINE, Embase and CINAHL, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.
Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co‐ordinator searches the register for each review using the topic list rather than keywords.
In addition, we will search ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) for unpublished, planned and ongoing trial reports. Our proposed search terms are detailed in Appendix 1.
Searching other resources
We will handsearch the congress abstracts of the American Society of Anesthesiologists (ASA, since 2000), the International Anesthesia Research Society (IARS, since 2003), and the European Society of Anaesthesiology (ESA, since 2004) congresses.
We will also search the reference lists of retrieved studies.
We will not apply any language or date restrictions.
Data collection and analysis
Selection of studies
Two review authors will independently assess for inclusion all the potential studies we identify as a result of the search strategy (Appendix 2). We will resolve any disagreement through discussion or, if required, we will consult a third person.
We will create a study flow diagram to map out the number of records identified, included and excluded.
Data extraction and management
We will use a form to extract data (Appendix 3). For eligible studies, two review authors will extract the data using the agreed form. We will resolve discrepancies through discussion or, if required, we will consult a third person. We will enter data into Review Manager software (RevMan 2014) and check for accuracy. When information regarding any of the above is unclear, we will attempt to contact authors of the original reports to provide further details.
Assessment of risk of bias in included studies
Two review authors will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) (Appendix 4). We will resolve any disagreement by discussion or by involving a third assessor.
(1) Random sequence generation (checking for possible selection bias)
We will describe for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.
We will assess the method as:
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low risk of bias (any truly random process, e.g. random number table; computer random number generator);
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high risk of bias (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number);
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unclear risk of bias.
(2) Allocation concealment (checking for possible selection bias)
We will describe for each included study the method used to conceal allocation to interventions prior to assignment and will assess whether the intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.
We will assess the methods as:
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low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
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high risk of bias (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth);
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unclear risk of bias.
(3.1) Blinding of participants and personnel (checking for possible performance bias)
We will describe for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We will consider that studies are at low risk of bias if they were blinded, or if we judge that the lack of blinding would be unlikely to affect results. We will assess blinding separately for different outcomes or classes of outcomes.
We will assess the methods as:
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low, high or unclear risk of bias for participants;
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low, high or unclear risk of bias for personnel.
(3.2) Blinding of outcome assessment (checking for possible detection bias)
We will describe for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We will assess blinding separately for different outcomes or classes of outcomes.
We will assess methods used to blind outcome assessment as:
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low, high or unclear risk of bias.
(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)
We will describe for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We will state whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information is reported, or can be supplied by the trial authors, we will re‐include missing data in the analyses which we undertake.
We will assess methods as:
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low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);
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high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomisation);
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unclear risk of bias.
(5) Selective reporting (checking for reporting bias)
We will describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found.
We will assess the methods as:
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low risk of bias (where it is clear that all of the study’s pre‐specified outcomes and all expected outcomes of interest to the review have been reported);
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high risk of bias (where not all the study’s pre‐specified outcomes have been reported; one or more reported primary outcomes were not pre‐specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);
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unclear risk of bias.
(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)
We will describe for each included study any important concerns we have about other possible sources of bias.
We will assess whether each study was free of other problems that could put it at risk of bias:
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low risk of other bias;
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high risk of other bias;
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unclear whether there is risk of other bias.
(7) Overall risk of bias
We will make explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Handbook (Higgins 2011). With reference to (1) to (6) above, we will assess the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings. We will explore the impact of the level of bias through undertaking sensitivity analyses ‐ seeSensitivity analysis.
Assessing the quality of the body of evidence using the GRADE approach
We will assess the quality of the evidence using the GRADE approach as outlined in the GRADE handbook in order to assess the quality of the body of evidence relating to the following outcomes for the main comparisons (remifentanil (PCA) versus (A) placebo or no treatment, (B) another opioid using the same mode of administration (PCA), (C) another opioid using a different mode (nurse‐/midwife‐controlled, short infusion) or route (IM/SC) of administration, (D) epidural analgesia or other central neuraxial blocks (e.g. CSE), (E) nitrous oxide (inhalational analgesia), (F) remifentanil using a different mode (IV) of administration.
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Satisfaction with pain relief
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Pain intensity
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Additional analgesia required (e.g. conversion to epidural analgesia)
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Conversion to caesarean delivery
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Adverse events for women (apnoea, respiratory depression)
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Adverse events for infants (Apgar scores less than seven at five minutes)
We will use the GRADEpro Guideline Development Tool to import data from Review Manager 5.3 (RevMan 2014) in order to create ’Summary of findings’ tables. A summary of the intervention effect and a measure of quality for each of the above outcomes will be produced using the GRADE approach. The GRADE approach uses five considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of the body of evidence for each outcome. The evidence can be downgraded from 'high quality' by one level for serious (or by two levels for very serious) limitations, depending on assessments for risk of bias, indirectness of evidence, serious inconsistency, imprecision of effect estimates or potential publication bias.
Measures of treatment effect
Dichotomous data
For dichotomous data, we will present results as summary risk ratio with 95% confidence intervals which will be obtained from the intervention and control event rates.
Continuous data
For continuous data the mean difference (MD) will be obtained from the difference between the intervention and the control group mean values with associated standard deviations (SD) if outcomes are measured in the same way between trials. We will use the standardised mean difference to combine trials that measure the same outcome, but use different methods. We further plan to include median values with interquartile range (IQR) in addition to mean values and SD in the analysis. In that case, we will obtain the mean and SD from median and IQR values in accordance with Higgins 2011. To assess the impact of the median data on the summary statistics, we will perform a sensitivity analysis.
Unit of analysis issues
Cluster‐randomised trials
We will include cluster‐randomised trials in the analyses along with individually‐randomised trials. We will adjust their standard errors using the methods described in the Handbook using an estimate of the intra‐cluster correlation co‐efficient (ICC) derived from the trial (if possible), from a similar trial or from a study of a similar population. If we use ICCs from other sources, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster‐randomised trials and individually‐randomised trials, we plan to synthesise the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely.
We will also acknowledge heterogeneity in the randomisation unit and perform a sensitivity analysis to investigate the effects of the randomisation unit.
Multi‐armed studies
We will overcome a unit‐of‐analysis error for studies that could contribute multiple comparisons by either combining groups to create a single pair‐wise comparison or split the shared group into two or more groups with smaller sample size, and include two or more reasonably independent comparisons if the presented data in the trials allow us to do so.
Dealing with missing data
For included studies, we will note levels of attrition. We will explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis.
For all outcomes, we will carry out analyses, as far as possible, on an intention‐to‐treat basis, i.e. we will attempt to include all participants randomised to each group in the analyses, and all participants will be analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial will be the number randomised minus any participants whose outcomes are known to be missing.
Assessment of heterogeneity
We will assess statistical heterogeneity in each meta‐analysis using the Tau², I² and Chi² statistics. We will regard heterogeneity as substantial if an I² is greater than 50% and either a Tau² is greater than zero, or there is a low P value (less than 0.10) in the Chi² test for heterogeneity.
Assessment of reporting biases
If there are 10 or more studies in the meta‐analysis, we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually. If asymmetry is suggested by a visual assessment, we will perform exploratory analyses to investigate it.
Data synthesis
We will carry out statistical analysis using the Review Manager software (RevMan 2014). We will use fixed‐effect meta‐analysis for combining data where it is reasonable to assume that studies are estimating the same underlying treatment effect: i.e. where trials are examining the same intervention, and the trials’ populations and methods are judged sufficiently similar. If there is clinical heterogeneity sufficient to expect that the underlying treatment effects differ between trials, or if substantial statistical heterogeneity is detected, we will use random‐effects meta‐analysis to produce an overall summary, if an average treatment effect across trials is considered clinically meaningful. The random‐effects summary will be treated as the average of the range of possible treatment effects and we will discuss the clinical implications of treatment effects differing between trials. If the average treatment effect is not clinically meaningful, we will not combine trials.
If we use random‐effects analyses, the results will be presented as the average treatment effect with 95% confidence intervals, and the estimates of Tau² and I².
Subgroup analysis and investigation of heterogeneity
If we identify substantial heterogeneity, we will investigate it using subgroup analyses and sensitivity analyses based on the comparators described above (Types of interventions). We will consider whether an overall summary is meaningful, and if it is, use random‐effects analysis to produce it. When sufficient data are present, we will compare subgroups by a mixed‐effects meta‐regression. We will use the R packages metafor for meta‐regression and mixed‐effects model analysis.
We plan to carry out the following subgroup analyses.
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Different methods and doses of remifentanil patient‐controlled analgesia (bolus versus only continuous infusion, regimen with a fixed dose versus dose‐escalating regimen, etc.).
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Different parenteral opioids (e.g. pethidine (meperidine) versus fentanyl).
Planned subgroup analysis will be restricted to the review's primary outcomes.
We will assess subgroup differences by interaction tests available within RevMan (RevMan 2014). We will report the results of subgroup analyses quoting the χ2 statistic and P value, and the interaction test I² value.
Sensitivity analysis
We plan to conduct a sensitivity analysis for the primary outcomes to assess the effect of trial quality. We will exclude studies with poor overall quality (high versus moderate versus low risk of bias, e.g. in randomisation, allocation concealment or blinding). We will explore the impact of studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis. If cluster‐randomised trials are to be included, we will conduct a sensitivity analysis (see Unit of analysis issues) to investigate the robustness of the results. Furthermore, we will perform a sensitivity analysis to assess the impact of the studies reporting continuous outcomes as median and IQR. Finally, we will carry out additional sensitivity analysis if there are issues identified throughout the review analysis which necessitate sensitivity analysis.
